Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53

SETDB1 is a histone H3K9 methyltransferase that has a critical role in early development. It is located within a melanoma susceptibility locus and facilitates melanoma formation. However, the mechanism by which SETDB1 regulates tumorigenesis remains unknown. Here we report the molecular interplay between SETDB1 and the well-known hotspot gain-of-function (GOF) TP53 R249S mutation. We show that in hepatocellular carcinoma (HCC) SETDB1 is overexpressed with moderate copy number gain, and GOF TP53 mutations including R249S associate with this overexpression. Inactivation of SETDB1 in HCC cell lines bearing the R249S mutation suppresses cell growth. The TP53 mutation status renders cancer cells dependent on SETDB1. Moreover, SETDB1 forms a complex with p53 and catalyses p53K370 di-methylation. SETDB1 attenuation reduces the p53K370me2 level, which subsequently leads to increased recognition and degradation of p53 by MDM2. Together, we provide both genetic and biochemical evidence for a mechanism by which SETDB1 regulates cancer cell growth via methylation of p53. SETDB1 is a histone methyltransferase and a role for the protein has been proposed in cancer. Here, the authors show that SETDB1 contributes to hepatocellular cancer by preferably forming a complex with mutant p53, resulting in di-methylation of a critical lysine residue and stabilization of the protein.

• Publication year

  2015

• Venue

  Nature Communications

• Publication date

  2015-10-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ncomms9651PMID 26471002PMCID 5426523
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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